Despite a low incidence, the economical burden of genetic diseases to families and the health system is extremely high, due to the cost of therapies ($100,000/patient-year) mostly suboptimal in alleviating these chronic conditions. This is the case for enzyme replacement therapies (ERTs) for treatment of lysosomal storage disorders (LSDs), prevalent genetic defects due to deficiency of lysosomal enzymes. ERT success is restricted to a few diseases affecting liver, spleen, and kidneys, where injected enzymes gain access via mechanisms of blood clearance. However, ERT delivery to the lungs, or brain for most common neurological LSDs, is hindered by the lack of affinity and transport of the enzymes to and into tissues. An example is ERT for Niemann-Pick disease (NPD) due to acid sphingomyelinase (ASM) deficiency, where lysosomal excess of sphingomyelin causes strong neurological disorder (type A phenotype) and affects lungs, liver and spleen (type B phenotype). Our goal is to develop strategies to improve ERT delivery to disease sites (lungs and brain). We propose to target ASM to intercellular adhesion molecule-1 (ICAM-1) expressed on the endothelium of all organs and cell targets in the parenchyma of tissues, and up-regulated in NPD. Our results indicate that classical endocytosis associated to vesicular transport from the blood to the tissue and the cell surface to lysosomes are defective in NPD, yet the non-classical pathway induced by ICAM-1 engagement by multivalent anti-ICAM/polystyrene prototype carriers is fully active in NPD. These prototypes enhance ASM targeting to lysosomes and sphingomyelin reduction in cultured endothelial cells and mice. A fraction of anti-ICAM prototype carriers are transported across endothelial cultures. We hypothesize that biocompatible ICAM-1- targeted carriers can provide vesicular transport of ASM across endothelial barriers (without affecting permeability) and endocytosis and lysosomal delivery in cells of the tissue parenchyma, attenuating NPD lung and brain phenotype. We will test this in cells and mouse models, using our new biocompatible PLGA carriers targeted to ICAM-1 by a peptide derived from its natural ligand, in Aims to evaluate and optimize: 1-Efficacy and safety of transendothelial transport, 2-Non-endothelial delivery, and 3-Effects in the NPD phenotype. The benefits of this strategy to transport therapeutics across endothelial barriers and into cells may transcend other LSDs and CNS treatments.